1-alkyl-4-(n-benzyl-n-beta-dialkyl-aminoethylamino)-piperidines and their production



Patented July 19, 1949 l-ALKYL- l- (N- BENZYL N BETA DIALKYL- AMINOETHYLAMINO) PIPERIDINES AND THEIR PRODUCTION Robert H. Reitsema, Kalamazoo, Mich., assignor to The Upjohn Company, Kalamazoo, Mich, a corporation of Michigan No Drawing. Application April 30, 1948, Serial No. 24,423

4 Claims. (01. 260 293) This invention relates to 1-alkyl-4-(N-benzyl- N beta dialkylaminoethylamino) piperidines and their salts with acids which are useful as therapeutic agents.

such as hydroxy, alkoxy, alkyl or amino groups.

The alkylation requires an elevated temperature and an acid-binding agent. In some instances an alkylation catalyst is helpful. The

The

After cooling, water may removed by filtration. The

The Water layer is ex- Many of the salts are The new 1-a1kyl-4-(N-benzyl-N-beta-dialkyl- 5 alkylation may be conducted Without a diluent, aminoethylamino) -piperidines may be reprealthough the use of a diluent, such as toulene, sented bythe formula: xylene, or cymene is preferred. Various cata- CHQHCH, lysts useful in alkylating amines may be em.- ployed, such as finely-divided copper-bronze. I 10 Anhydrous metal carbonates or bicarbonates are QM K useful acid-binding agents, those of the alkali metals being preferred. An excess of the starting amine may also be employed for acid-binding purposes. The alkylation is carried out by mix- 5 ing the reactants together in substantially equimolar proportions with or without a diluent and E8 heating the mixture, at temperature of about 150- wherein n is zero or a small number from one to 170 d ees Centigrade being t sui le. eight, inclusive, period of heating is not of critical importance,

The tertiary amines herein described are high- 20 various times from 5 to 50 hours being suitab eboiling substances which are viscous liquids or The reaction mixture may be worked up in solids at room temperature, readily soluble in ways known to the art. most common organic liquids, and only slightly be added and the copper-bronze or other catasoluble in water. The compounds readily form y if p y addition salts with mineral acids such as hydro- 25 early removal of catalyst aids in separation of chlo-ric, hydrobromic, and sulfuric; with organic the water layer from the d uent l yer conta carboXylic acids, such as acetic, lactic, tartaric, s o of the p and succinic; and strongly acidic phenolic acids aeted Wit e e benzene, toulene or Xy e. such as picric acid. The acid salts are usually n the organic extract combined with the diluent water soluble, the hydrochlorides in some inaye the combined solu ions dr ed, d t e p odstances having such a strong affinity for water not isolated and purified by dist llation. Other that it is difficult to obtain them in anhydrous Ways of recovering the 1-alkyl-4-(N-benzyl-N- form. The salts, however, may be readily prebeta-dialkylaminoethylamino) piperidines will be pared in aqueous solution. apparent to those familiar with the art.

The compounds of this invention, having three Acid salts of the amines are prepared in varistrongly basic tertiary amino groups, are capable ous Ways known to the art. If an aqueous soof forming salts with from one to three equivalution of the salt is desired, the amino compound lents of an acid. The monoand di-acid salts may be titrated with acid until the resulting somay be formed by mixing a stoichiometric quanlution has attained the desired pH. If it is detity of the acid with the free amine and. evapo- -10 sired to isolate the salt, this may be done by rating to dryness. An excess of acid gives only evaporating its solution to dryness or a solution the tri-acid salt of the base. When the salt is of the amine may be reacted with a solution of used for therapeutic properties, since the theraan acid, the solvent chosen being one in which peutic activity resides in the basic portion of the the amine salt is insoluble, whereupon the inmolecule, the acid groups attached thereto are soluble salt precipitates. of significance only in that they should be nonquite hygroscopic in nature. toxic and in that they dilute the effectiveness of The following examples illustrate the inventhe molecule, as determined on a Weight basis, tion but are not to be construed as limiting. in proportion to theirnumber. 1

The 1-alkyl-4-(N-benzyl-N-beta-dialkylaminoso Emmw 1 ethyl 4 (N hem dzmethyzammo ethylamino) -piperid.ines may be prepared by the alkylation of a l-alkyl--(beta-dialkylaminoethylamino) -pipericline with a benzyl halide, preferably benZyl bromide or benzyl chloride. The benzyl group may also contain substituents ethylammo) -29iperidine Thirty-four and five-tenths grams of l-ethyl- 4-piperidone [Fuson, Parham and Reed, J. Am. Chem. Soc. 68, 1239 (1946)] and 25.2 grams of beta-dimethylaminoethyl amine were thoroughly mixed at a temperature between 15 and 25 degrees centigrade. To the reaction mixture was then added 100 milliliters of absolute ethyl alcohol and the alcoholic solution reduced at room temperature with hydrogen under pressure (50 pounds per square inch) and Adams platinum oxide catalyst. Absorption of hydrogen was complete after about two hours, whereupon the catalyst was removed by filtration and the resulting 1 ethyl 4 (N beta-dimethylaminoethylamino) -piperidine, boiling at 136-139 degrees centigrade at 18 millimeters of mercury pressure,

was melted at 238.5-239 degrees centigrade with decomposition. In the same manner are prepared the diethylaminoethyl, dipropylaminoethyl, diis o p ropylarninoethyl, methylethylaminoethyl, and other similar l-alkyl-piperidines, by substituting the selected amine for beta-diethylaminoethyl amine in the above example.

Example 2.1-ethyZ-4-iN-benzyl-N-dimeihylaminoethylamz'no) -piperzdine To a stirred suspension of 58.0 grams of 1- ethyl 4-beta-dimethylaminoethylamino) piperidine'dissolved in 500 milliliters of xylene, 40.2 grams of anhydrous potassium carbonate and 0.5 grams 7 of finely-divided copper-bronze powder, 49.8 grams of benzyl bromide, was added over a period of thirty minutes. After addition of benzyl bromide, the suspension was heated with continued stirring to 150-170 degrees 'centigrade for about fortyhours. Upon cooling to room temperature, 25 milliliters of water was added slowly, copper-bronze catalyst removed by filtration, xylene and water layers separated, and the aqueous layer extracted with ether. The ether extract was combined with the xylene, dried, and l-ethyll- (N-benzyl-N-beta-dimethylaminoethylamino) piperidine obtained as a viscous oil boiling at 185 188 degrees centigrade 0.7 millimeters of mercury by removal of solvent. The solid, which partially crystallized from the oil in the receiver, melted at 99-100 degrees centigrade.

The hydrochloride was obtained by mixing an ether solution'of 1-ethyl-4-(N benzyl-N-beta-di methylarninoethylamino) piperidine with ether solution containing the quantity of hydrogen chloride calculated to form the trihydrochloride. A hygroscopic solid was obtained upon removal of the solvent, on which a definite melt ing point could not be determined. The tripicrate, after crystallization from ethyl acetate, melted at 193-195 degrees centigrade with decomposition.

isolated .by distillation[ The tripicrate vpresent invention without departing from the.

Example 3.-1-methyl -4- (N-benzyl-N-betadiethylaminoethylamino) -pzperidine In the same manner as given for Example 2, equimolar quantities of 1-methy1-4-(N-beta-diethylaminoethylamino)-piperidine and benzyl bromide are heated in xylene in the presence of potassium carbonate and a copper-bronze catalyst to yield the desired 1-methyl-4-(N-benzyl- N beta diethylaminoethylamino) piperidine, which may be separated as a high- Viscous liquid and converted to acid salts such as the tripicrate, by the procedure indicated in the foregoing. 7

Other. compounds within the scope of the invention which may be prepared according to the iven procedure by reacting a benzyl halide and the selected 1-alkyl-4- (N-betadialkylaminoethylamino) -piperidine are the l-methyl 1-propyl-, 1-isopropyl-, 1-buty1-, 1-amyl-, and like 4-(N- benzyl-N-beta-dimethylaminoethylamino) -piperidines, 4 (N-benzyl- N beta-diethylaminoethylamino) -piperidines, 4- (N-benzyl-N-beta dipropylaminoethylamino) -piperidines, 4 (N-benzyl- N-beta-diisopropylaminoethylamino) -piperidines,

4 (N benzyl-N-beta-dibutylaminoethylamino) piperidines, 4- (N-benzyl-N-beta-methylethylaminoethylamino) -piperidines, and acid salts thereof. Various modifications may be made in the spirit or scope thereof, and it isto be understood that I limit myself only as defined by the appended claims; Y

I claim: 7

1. A compound selected from the group consisting of (a) 1-alkyl-4-(N-benzyl-N-beta-dialkylaminoethylamino) -piperidines, wherein the 7 alkyl groups contain from one to eight carbon atoms, inclusive, and (b) acid salts thereof.

2. 1-ethyl-4- (N-benzyl-N-beta-dimethylaminm ethylamino) -piperidine.

' 3. l-ethyll-(N-benzyl-N-beta-dimethylaminoethylamino) -piperidine tripicrate.

4. The process for the preparation of a. 1-alkyl- 4-(N-benzyl-N-beta dialkylaminoethylamino) piperidine which includes the step of heating a I-alkyI-4-(N-beta dialkylaminoethylamino) -piperidine with a benzyl halide, selected from the group consisting of the bromide and chloride, in the presence of an acid binding agent to produce 1-alkyl-4-(NJoenzyl-N-beta-dialkylaminoethylamino) -piperidine.

' ROBERT H. REITSEMA,

No references cited, 

